Atherosclerosis is now recognized as a chronic inflammatory disease, and Project Leaders of our PPG have contributed seminal information to the widespread recognition that immune mechanisms play a central role in modulating atherogenesis. Leveraging information gained in the first cycle, we propose studies of the roles of macrophages, T cells, B cells, Natural antibodies (NAbs) and innate TLRs on inflammation and atherogenesis. Project 1 will pursue their seminal observations that foam cell formation in the peritoneum of cholesterol-fed mice exhibited an unexpected suppressed inflammatory gene phenotype, which was due to accumulation of desmosterol, a potent LXR ligand, leading to inhibition of inflammatory gene expression. They will study the transcriptional mechanisms by which this occurs, and determine if novel therapeutic approaches can be exploited based on use of desmosterol-like agents that inhibit inflammatory activity. Project 2 will pursue their findings that PPARy is expressed in Treg cells in peri-aortic adipose tissue, which surrounds the aorta at key anatomical sites where atherogenesis is enhanced. They will explore the hypothesis that this is mediated by a proinflammatory gene network that can be modulated at the transcriptional level by PPARy and REVERBa/p, regulating vital functions of Treg and Th17 cells. Project 3 will pursue their recent identification that oxidation specific epitopes (OSE), as occur on OxLDL or apoptotic cells, are major targets of innate NAbs. They will focus on defining the prevalence of OSE-NAbs in humans and mice, the mechanisms by which they are atheroprotective, and define transcriptional mechanisms by which GR and LXR regulate B-1 cells, which generate NAbs. Overall, these studies should provide vital insights into novel and as yet unexplored mechanisms by which adaptive and innate immunity regulates inflammation and atherosclerosis, and may lead to novel diagnostic and therapeutic approaches for cardiovascular disease.